Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice

Abstract

The possible role of the CB2 receptor (CB2 r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB 2 r in the regulation of such behaviors. Mice lacking the CB 2 r (CB2 KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D2 (D2 r), adrenergic-α 2C (α 2C r), serotonergic 5-HT 2A and 5-HT 2C receptors (5-HT 2A r and 5-HT 2C r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB 2 r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it normalized the PPI deficit in CB2 KO mice. CB2 KO mice presented increased D2 r and α 2C r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT 2C r gene expression in the dorsal raphe (DR), and 5-HT 2A r gene expression in the PFC. Chronic risperidone treatment in WT mice left α 2C r gene expression unchanged, decreased D2 r gene expression (15 g/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB2 KO, the gene expression of D2 r in the PFC, of α 2C r in the LC, and of 5-HT 2C r and 5-HT 2Ar in PFC was reduced; 5-HT 2C r and 5-HT 2A r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB2 r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB2 r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders. © 2011 American College of Neuropsychopharmacology. All rights reserved.